The blood brain barrier prevents many compounds in the blood stream from entering the tissues and fluids of the brain. It is generally recognized that nature provides this mechanism to insure a toxin-free environment for neurologic function. A functional barrier in addition to an anatomic barrier, the BBB is of great importance for the maintenance of a constant environment for optimal CNS function. Most metabolic substrates (i.e. sugars and amino acids) are hydrophilic, and traverse the BBB only by specific carrier-mediated transport systems, which are expressed at both the luminal and abluminal sides of BBB endothelial cells. Other molecules traverse the blood brain barrier more freely. As a general rule, the blood brain barrier excludes hydrophilic and allows passage of lipophilic molecules.
Small molecules pass through the endothelial monolayer of the blood brain barrier permeability more freely than large molecular weight compounds. This is in particular true for proteins. In fact, both sites of cerebrospinal fluid (“CSF”) formation, the choroid plexus as well as blood brain barrier endothelial cells, allow negligible passage of protein. Macromolecules such as polypeptides/protein, can cross an endothelial cell barrier primarily in three ways: between the cells through cell-cell junctions (paracellular pathway), through the EC, via pores (fused vesicles), or transcellularly via shuttling specific vesicles and receptors. Electron microscopic evidence suggests that macromolecules are shuttled across the endothelial barrier via vesicles.
Unfortunately, a plethora of potentially useful therapeutic agents are blood brain barrier impermeant, severely hampering their potential for aggressive treatment of a broad spectrum of neurological disorders, including brain tumors. The BBB prevents delivery to the brain of compounds, such as chemotherapeutics, pharmaceuticals, neuropharmaceuticals, potential neuropharmaceuticals, and other neurologically active agents, that might otherwise remedy or modify activities, diseases, and disorders in the brain. Interestingly, in many diseased states, the blood brain barrier is less restrictive compared to normal subjects, and this feature allows a window of therapeutic intervention. Diseases in which increased BBB permeability have been reported include neoplasia, ischemia, tumors, hypertension, dementia, epilepsy, infection, multiple sclerosis, and trauma.
The CSF contains proteins but their concentration is much less than that in plasma. In fact, the concentration in CSF is so low that it is customary to regard this compartment as an essentially protein-free fluid, comparable with the aqueous portion of the eye or normal urine. For more than 100 years the analysis of cerebrospinal fluid has been used to monitor, diagnose or detect changes in neurological function in the brain. This approach is based on the concept of a segregated protein content in plasma-vs-brain. When the separation mechanisms that allow the formation of such an outstanding gradient for protein fluxes from the plasma to the brain fail, appearance of serum protein into the CSF will occur. Sampling of cerebrospinal fluid is commonly achieved by invasive techniques, such as “spinal taps”, whereby a small amount of CSF is drained usually from the lumbar portion of the spinal cord. Samples can be intra surgically taken from the ventricles or from the sub-arachnoid space in the brain. An obvious limitation of intrathecal detection of blood brain-barrier intactness resides in the fact that sampling of CSF is invasive, and that the sample itself may be contaminated by the procedure. In addition, it has been known for a long time that a gradient in protein content exists from the brain to the lumbar cord. In fact, the concentrations of protein in segments distal to the site of CSF reduction (ventricles) are known to be much higher. It appears that, at least in part, the increased protein in the lumbar compartment of the CSF is due to a combination of protein secreted by parenchymal cells plus a small amount of protein leakage across the blood brain-barrier.
Ongoing or incipient systemic dysfunction of the heart, pancreas, liver or kidney can often be detected with the help of biochemical markers, whose specificity and known kinetics permit diagnostic and prognostic evaluation. The complexity of CNS function and the multiple kinetic parameters involved in bio-distribution across the blood brain barrier and within the brain parenchyma imposes a considerable burden for the interpretation of putative biochemical markers present in serum or cerebrospinal fluid. While changes in the composition of cerebrospinal fluid are commonly used to diagnose a variety of neurological diseases, the invasiveness of the procedures involved greatly decrease their usefulness
It would be useful to have a predictable and reliable peripheral marker of blood-brain barrier integrity in order to monitor the neurological status of a subject and to predict outcome and/or to adjust the therapy.